1. Field of the Invention
The present invention relates to novel heterocyclic compounds possessing valuable pharmaceutical activity, particularly dopamine agonist and antihypertensive activities. Novel intermediates, used for preparing the active therapeutic agents, also possess valuable therapeutic properties and are also within the scope of this invention. The present invention is also directed to pharmaceutical compositions containing the novel compounds as well as a method of treating hypertension to a host, including humans by administering to the host an anti-hypertensive effective amount of the compounds of the present invention or salts thereof.
2. Background of the prior art
Azaspirodecanes and azaspirononanes have generally been used as stabilizers. For example:
U.S. Pat. No. 3,959,291 to Cook discloses compounds of the formula: ##STR2## wherein R.sub.1 and R.sub.2 taken together with the carbon to which they are bound form a cycloalkyl residue having from 5 to 12 carbon atoms in the ring, Y is among other things, an alkyl residue having from 1 to 20 carbon atoms, aralkyl having from to 12 carbon atoms and R.sub.3 is hydrogen or a straight or branched chain alkyl residue. These compounds are disclosed as being useful as stabilizers.
Swiss Patentschrift No. 469736 discloses compounds of the formula: ##STR3## wherein X and Y are independently oxygen or sulfur; R.sub.1 is a hydrocarbon chain with 2 to 11 carbon atoms and the total number of carbon atoms in X and Y range from 2-4 carbons; R.sub.2 is hydrogen or a methyl group; R.sub.3, R.sub.4 or R.sub.5 are hydrogen, lower alkyl or alkoxy or R.sub.3, R.sub.4, R.sub.5 taken together are 3-4 methylenedioxy and A is alkylene group having up to 5 carbon atoms.
Brunetti, et al. in U.S. Pat. No. 4,105,626 disclose 4-oxopiperidines of the formula: ##STR4## wherein n is 1 or 2, R.sub.1 is alkyl having 2 to 6 carbon atoms; R.sub.2 is alkyl having 1 to 6 carbon atoms; R.sub.3 is alkyl having 1 to 9 carbon atoms, phenyl, benzyl or phenylethyl; R.sub.4 is alkyl having 1 to 6 carbon atoms or R.sub.3 and R.sub.4 taken together with the carbon atom which they are attached form a cyclopentyl or cyclohexyl group; R.sub.5 is alkyl having 1 to 5 carbon atoms, alkenyl and alkynyl; R.sub.6 is hydrogen, or alkyl having 1 to 5 carbon atoms, alkenyl and alkynyl; X is hydrogen, alkyl having 1 to 8 carbon atoms and Y is C(R.sub.11)(R.sub.12)--CH(R.sub.13)--, --CH(R.sub.11)--CH.sub.2 --C(R.sub.12)(R.sub.13), --CH(R.sub.12)--CH.sub.2 --C(R.sub.11)(R.sub.13)--, --CH.sub.2 --C(R.sub.11)(R.sub.12)--CH(R.sub.13 )--, wherein R.sub.11 is hydrogen, methyl or CH.sub.2 OR.sub.14, R.sub.12 is hydrogen, methyl or ethyl, R.sub.13 is hydrogen, methyl or ethyl and R.sub.14 is hydrogen or an acyl residue. These derivatives are useful as stabilizers for organic polymers against light induced deterioration.
U.S. Pat. No. 4,014,887 to Randell, et al. discloses compositions containing compounds of the formula: ##STR5## wherein R.sub.1 and R.sub.2 are the same or different and each is a straight or branched alkyl residue having from 1 to 12 carbon atoms or R.sub.1 and R.sub.2 together with the carbon to which they are attached form a cycloalkyl group having from 5 to 12 carbon atoms or a piperdine derivative of the formula: ##STR6## wherein Y' is a straight or branched alkyl residue having from 1 to 20 carbon atoms, an alkenyl group, or alkynyl group having from 7 to 12 carbon atoms, an aralkyl group, etc. It is alleged that the compositions herein possess light stability.
Some researchers have recognized that azaspirodecanes and azaspirononanes have medicinal properties. For example:
Australia Patent No. 248763 discloses compounds of the formula: ##STR7## wherein R.sub.1 and R.sub.2 taken together may form a ring provided by a group selected from (CH.sub.2).sub.4, (CH.sub.2).sub.5 and (CH.sub.2).sub.6 ; R.sub.3 is hydrogen, methyl, ethyl, and propyl, and R.sub.4, R.sub.5 and R.sub.6 are independently hydrogen, alkoxy, hydroxy and its esters and have from 1 to 4 carbon atoms or R.sub.4, R.sub.5 and R.sub.6 may together form a group selected from methylenedioxy and ethylenedioxy and n is an integer from 1 to 3. The compounds therein are disclosed as being useful in the treatment of hypertension.
U.S. Pat. No. 3,282,947 to Grogan discloses unsymmetrically substituted 3,9-diazaspiro(5,5)undecanes of the formula: ##STR8## wherein R is among other groups, alkyl, aryl, aroyl, aralkyl, cycloalkyl, heterocyclic alkyl and R' is R or H. The compounds of said formula are alleged to possess useful medicinal utility, and may be useful as local anesthetics, antispasmodics, antihistaminics and hypotensives.
U.S. Pat. No. 3,418,324 to Rice, et al. discloses compounds of the formula: ##STR9## wherein A is selected from the group consisting of monocarbocylic rings having 5 to 15 carbon atoms, hexahydrohydrindenyl and decahydronaphthyl; X is at least one substituent on ring A selected from the group consisting of alkyl of up to 12 carbon atoms, lower alkoxy, lower alkenyl, cycloalkyl of up to 6 carbon atoms, phenyl and naphthyl. Said compounds are disclosed as being intermediates in the preparation of products having medicinal properties.
However, heretofore no attempt has been made to prepare the novel azaspirononanes and azaspirodecanes of the present invention. Furthermore, no one previously has recognized that the spiro compounds of the present invention simultaneously possess anti-hypertensive activity through dopamine receptor stimulation, and unexpectedly lack any central dopamine stimulating activity which is concomitant with most dopamine agonists. Finally, no one recognized heretofore that spiro compounds can be used as important intermediates in the preparation of octahydroindolo [3,4-f,g] quinoline compounds, which also possess dopamine agonist activity, as described hereinbelow.
Compounds based on the ergoline ring system: ##STR10## has been shown to have a variety of pharmaceutical activities. For example, the amides of lypergic acid have valuable and unique pharmacological properties and include the naturally occurring peptide alkaloids, ergocornine, ergokryptine, ergonovine, ergocristine, ergosine, and ergotamine synthetic oxytocic alkaloids, such as the synthetic hallucinogenlyseric acid diethylamide or LSD.
Semonsky, et al. in U.S. Pat. No. 3,732,231 disclose D-6-methylergolines of the formula: ##STR11## wherein R is chlorine, CN, COOH, COCl, COOCH.sub.3, CONHNH.sub.2, or CON.sub.3 and R.sub.1 is hydrogen, where in the case that R is COOH, R.sub.1 may be CH.sub.3. The reference teaches that the compound D-6-methyl-8-cyanomethylergoline has antifertility activity.
Bernardi, et al. in U.S. Pat. No. 3,228,939 disclose ergoline derivatives of the formula: ##STR12## wherein R is hydrogen or nethyl; R' is CONH.sub.2 or CH.sub.2 NHR" and R" is a hydrogen atom or an acylate radical derived from an aliphatic, cycloaliphatic, aromatic or heterocyclic carboxylic acid having 1 to 10 carbon atoms. The compounds are alleged to exhibit oxytocic, antienteraminic, adrenolytic, hypotensive and sedative activity
Closely related is U.S. Pat. No. 3,228,942 to Camerino, which discloses 6-methyl and 1,6-dimethyl-8-aminomethylergolines of the formula: ##STR13## wherein R is hydrogen or methyl, R' is an alkyl, cycloalkyl or aryl radical having from 1 to 9 carbon atoms and R" is a radical of an aliphatic, cycloaliphatic, aromatic or heterocycliccarboxylic acid having from 1 to 10 carbon atoms The compounds herein are alleged to show oxytocic, antienteraminic, adrenolytic, hypotensive and sedative activity.
Arcamone, et al. in U.S. Patent No. 3,646,046 disclose 1,6-dimethyl-10-alpha-ergoline derivatives of the formula: ##STR14## wherein R is selected from the group consisting of the radical of an aliphatic, cycloaliphatic, aromatic and heterocyclic organic acid having from 1 to 10 carbon atoms. Again these compounds are alleged to possess antienteraminic, oxytocic, adrenolytic, hypotensive and sedative activity.
British Patent No. 976065 is directed to 6-methyl and 1,6-dimethyl lumiergoline derivatives of the formula: ##STR15## wherein R is hydrogen or methyl and R' is CH.sub.2 NHR" and R" is hydrogen or a radical of an aliphatic, cycloaliphatic, aromatic or heterocyclic carboxylic or sulfonic acid having from 1 to 10 carbon atoms. The reference teaches that said compounds exhibit oxytocic, antienteraminic, adrenolytic, hypotensive and sedative activities.
U.S. Pat. No. 3,236,852 to Bernardi, et al. disclose esters of 6-methyl and 1,6-dimethyergoline compounds of the formula: ##STR16## wherein R is hydrogen or methyl and R' is an aliphatic, cycloaliphatic, aromatic or heterocyclic acid having from 3 to 10 carbon atoms. The compounds herein are alleged to exhibit oxytocic, antienteraminic, adrenolytic, hypotenstive and sedative activity.
Hofmann, et al. in U.S. Pat. No. 3,232,942 disclose 1-substituted lysergols of the formula: ##STR17## wherein R.sub.1 is alkyl containing 1-4 carbon atoms, an aralkyl, alkenyl, and ##STR18##
U.S. Pat. No. 3,238,211 to Camerino, et al. discloses alkylamino derivatives of 6-methyl and 1,6-dimethylergolines of the formula: ##STR19## wherein R is hydrogen or a radical of an organic carboxylic or sulfonic acid of the group of aliphatic, cycloaliphatic, aromatic or heterocyclic acids having from 1 to 10 carbon atoms and R' is hydrogen or methyl. Said compounds are alleged to have oxytocic, antienteraminic, adrenolytic, hypotensive and sedative activities.
European Patent Application No. 5646 is directed to tetrahydroindoloisoquinolines of the formula: ##STR20## wherein the moiety A-B represents a group of the formula CH.sub.2 NR.sub.3 or NR.sub.3 CH.sub.2 ; R.sub.3 represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl; R represents hydrogen, alkyl or cycloalkyl; R.sub.1 and R.sub.2 each represent hydrogen or taken together a chemical bond and X is hydrogen or halogen. The compounds herein are alleged to be useful in the treatment of disorders of the central nervous system.
Arcari, et al. in U.S. Pat. No. 3,904,634 disclose bromoergolines of the formula: ##STR21## wherein R.sub.1 is hydrogen or methoxy, R.sub.2 is CONH.sub.2 or CH.sub.2 X; X is NH.sub.2 OH, or ##STR22## R.sub.4 is aryl or heterocyclic or ##STR23## and R.sub.5 and R.sub.3 are hydrogen or methyl. The compounds herein are alleged to exhibit adrenolytic and antienteraminic activity
British Patent No. 981827 is directed to lumilysergol derivatives of the formula: ##STR24## wherein R is hydrogen or methyl, R' is hydrogen or loweralkyl and R" is hydrogen or a radical of aliphatic, cycloaliphatic, aromatic or heterocyclic carboxylic acids having from 1 to 10 carbon atoms. The compounds herein are alleged to exhibit oxytocic, antienteraminic, adrenolytic, hypotensive and sedative activities.
U.S. Pat. No. 3,879,554 to Temperilli discloses 1,6-dimethyl-8-.beta.-(5-bromonicotinoyloxymethyl)-10.alpha.-methoxyergoli nes of the formula: ##STR25## wherein R is methyl or aryl. Said compounds are alleged to be useful in inhibiting blood platelet aggregation and in the treatment of cerebral and peripheral metabolic vascular disorders.
British Patent No. 1,107,156 is directed to ergoline carboxylic acids of the formula: ##STR26## wherein XY represents the radical of the formula CH--CH.sub.2 --CH, or ##STR27## and R represents the radical (CH.sub.2).sub.n --COOH where n is equal to 0 or 1. No utility is disclosed in said patent.
Patentschrift No. 203721 discloses compounds of the formula: ##STR28## wherein R.sub.1 is alkyl, R.sub.2 is alkyl and R.sub.3, is among other things, hydroxymethyl. The compounds herein are alleged to be vasoconstrictors and to have prolactin-inhibiting properties.
Offenlegungsschrift No. DE3001752 discloses 8-substituted 6-methyl-10-.alpha.-H ergolines of the formula: ##STR29## wherein R.sub.1 is NH--CO--NR.sub.2, CO--NH--NR.sub.2, CO--NR.sub.2 and CH.sub.2 OR.sub.2 and R.sub.2 is hydrogen, methyl or ethyl.
European Patent Application No. 2087889 discloses naphthyridine derivatives of the formula: ##STR30## wherein R.sub.1 is in the 9 or 10 position and represents hydrogen, halogen or alkyl or alkoxy radical and R.sub.2 is a hydrogen or alkyl radical. The compounds herein are alleged to possess antianoxia action and psychotropic action.
U.S. Pat. No. 3,299,078 to Pachter discloses compounds of the formula: ##STR31## wherein R.sub.1 represents hydrogen, halogen, lower alkyl, loweralkoxy or trifluoromethyl; R.sub.2 represents hydrogen, loweralkyl or phenyl; R.sub.3 represents hydrogen or loweralkyl; R.sub.4 represents hydrogen, loweralkyl or benzyl and A represents --CH.sub.2 -- or --CH.sub.2 CH.sub.2 --. The compounds herein are alleged to have analgesic, anti-pyretic, anti-inflammatory, anti-serotonin and central nervous system stimulant activities.
European Patent Application No. 4664 is directed to ester derivatives of lysergol having the formula: ##STR32## wherein R is an aliphatic, cycloaliphatic, aromatic, heterocyclic radical having up to 10 carbon atoms. The compounds herein are alleged to have adrenolytic and anti-serotonic activity.
Patentschrifft No. 160804 discloses the following compound as a starting material: ##STR33## wherein R.sub.1 is alkyl, hydroxymethyl, alkoxymethyl, alkoxy carbonyl or a substituted amido group.
Semonsky, et al. in U.S. Patent No. 3,732,231 disclose 8-(beta-aminoethyl)ergolines of the formula: ##STR34## wherein R.sub.1 is an hydrogen atom or an acyl group and R.sub.2 is hydrogen or methyl. The compounds therein are alleged to have anti-inflammatory and hypotensive activity.
Kornfield, et al. in U.S. Pat. No. 4,246,265 disclose a group of dopaminergic drugs that are allegedly used to treat Parkinsonism and to inhibit prolactin secretion, having the formula: ##STR35## wherein Y is oxygen or sulfur and R.sub.1 is n-propyl.
Karepelka discloses, in an article in the Collection of Czechoslov Chem. Commum, 42, 1977 pp. 1209-1215, 6-alkylergoline derivatives of the formula: ##STR36## wherein R.sub.1 and R.sub.2 are methyl; or R.sub.1 is methyl and R.sub.2 is ethyl, n-propyl, isopropyl, butyl, isobutyl and heptyl; or R.sub.1 is methyl and R.sub.2 is hydrogen; or R.sub.1 is CH.sub.2 OH and R.sub.2 is ethyl, n-propyl, and n-butyl; or R.sub.1 is CH.sub.2 Cl and R.sub.2 is ethyl, n-propyl and n-butyl. The compounds described herein wherein R.sub.1 is methyl exhibit an antilactating and an anti-fertility effects in rats.
Offenlegungsschrift No. DE 3403067 discloses ergoline derivatives of the formula: ##STR37## wherein (a) R.sub.1 is hydrogen or methyl; R.sub.2 is alkyl containing 2 to 8 carbon atoms and can be substituted with 1, 2 or 3 halogen atoms, alkenyl containing 3 to 8 carbon atoms, cycloalkyl, cycloalkylalkyl or alkylcycloalkyl and R.sub.3 is methyl, hydroxymethyl, acyloxymethyl, halogenomethyl or methylene or (b) R.sub.1 can be alkyl with 2 to 8 carbon atoms which can be substituted with 1, 2 or 3 halogen atoms, alkenyl with 3 to 8 carbon atoms, cycloalkyl with 4 to 7 carbon, cycloalkylalkyl or alkylcycloalkyl; R.sub.2 can be a cyclic group, hydrogen, alkyl containing 1, 2 or 3 halogen atoms, alkenyl containing 3 to 8 carbon atoms, cycloalkyl containing 4 to 7 atoms, cycloalkylalkyl or alkylcycloalkyl containing 4 to 7 ring carbon atoms, phenyl or phenylalkyl and R.sub.3 is methyl, hydroxymethyl, acyloxymethyl, alkoxymethyl, halogenomethyl or methylene. The compounds disclosed herein can have a double bond in position 8-9 or a double bond in position 9-10 or may have no double bonds at all in either of those positions.
Bach, et al. in U.S. Patent No. Re. 30,218 disclose 8,8,9-6-methyl-ergolines of the formula: ##STR38## wherein R is alkyl, carbo(C.sub.1 -C.sub.13) alkoxy, chloro or bromo; R' is carboxyl, carbo (C.sub.1 -C.sub.3) alkoxy or CH.sub.2 Z wherein alkyl is (Cl-C3), and Z is H, OH, CN, OSO.sub.2 alkyl, Y-phenyl or Y-alkyl wherein Y is S or O and R" and R'" when taken singly are hydrogen and when taken together with the carbon atoms to which they are attached form a double bond. It is alleged that the compounds therein are useful as prolactin inhibitors and/or have activity in the central nervous system.
European Patent Application No. 185392 discloses ergoline compounds of the formula: ##STR39## wherein the line between carbon-9 and carbon-10 is a single or double bond, R.sub.2 is hydrogen, C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.7 -acyl, R.sub.3 is hydrogen, chlorine, bromine and R.sub.4 is C.sub.2 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl C.sub.1 -C.sub.3 alkyl, C.sub.3 -C.sub.6 alkenyl or C.sub.2 -C.sub.6 alkynyl. The compounds are disclosed to have antidiodopaminergic activity.
European Patent Application No. 43811 discloses indolonaphtyridines of the formula: ##STR40## wherein R is hydrogen or alkyl group of 1-6 carbon atoms, R.sub.4 is a hydrogen atom, R.sub.2 is a hydrogen atom R.sub.3 is hydrogen or a hydroxy group and R.sub.2 and R.sub.3 together form a carbon bond. It is alleged herein that the compounds are active medicaments.
However, heretofore, no attempt has been made to prepare the indoloquinolines of the present invention. Moreover, no one has recognized that the indoloquinolines of the present invention posses potent anti-hypertensive activity through peripheral dopamine receptor stimulation, without any central dopamine stimulating activity.